Narcotic opiate analgesics remain the mainstay of presently available drug regimens used to alleviate moderate to severe pain. Opiate analgesics produce a characteristic antinociceptive response in various animal species (including homo sapiens) through activation of specific receptors in the central nervous system. It is well established that activation of one or more of these receptors produces antinociceptive effects in relevant animal models of pain assessment.
Multiple types of opioid receptors have been shown to co-exist in higher animals, of which at least three distinct classes have been characterized, with evidence for additional classes or subclasses: mu (.mu.), kappa (K) and delta (.delta.). For example, see W. Martin et al., J. Pharmacol. Exp. Ther., 197, p. 517(1975); and J. Lord et al., Nature (London), 257, p. 495 (1977). The .mu. receptor is located in the brain and appears to be involved in the analgesic effect of morphine-like drugs. .kappa.-Receptor activation in the brain and spinal cord appears capable of producing analgesia, particularly at the spinal level. The .delta.-receptor is found in some peripheral tissues in addition to the brain and spinal cord, and shows a differentiating affinity for endogenous opioid peptides known as enkephalins. Finally, although it is doubtful that .sigma.-receptors are strictly "opioid" in character as they are activated by non-opioid compounds, the majority of psychotomimetic effects of opioid drugs, such as dysphoria and hallucinations, appear to be mediated by this class of receptors.